Why supplement with B12? Like many nutrients, vitamin B12 plays a number of crucial roles within the human body. While a deficiency is most commonly associated with fatigue, signs and symptoms of tingling in the extremities, restless leg syndrome, anemia or homocysteinema can be indicative of a B12 deficiency. Moreover, many conditions show clinical improvements through supplementation with B12, even when serum B12 lab values may be considered ‘within normal limits’. What are the different forms of B12? There are generally 3 forms of supplemental B12: cyanocobalamin, hydroxycobalamin and methylcobalamin. Each of these forms has their own advantages and disadvantages,
MYTHS AND CONTROVERSIES
Social media posts often warn us of the dangers of certain foods, products and supplements. Although some of these have merit, many are based on misinterpreted research or poorly designed studies. This has often been the case with B-Vitamins. Although they have a reputation for being “energy boosters,” and have many vital functions in the body, studies and headlines have been published that link supplemental B vitamins (vitamins B2, B6, B12, and folic acid) with autism and cancer. Let’s take a closer look to find out what the research is actually showing.
DOES FOLIC ACID INTAKE INCREASE THE RISK OF AUTISM?
THE ROLE OF FOLIC ACID
Before we address the autism myth, it’s essential to understand folic acid’s role in the body.
In pregnancy, there is a greater need for folate because the fetus requires it. Folate (aka vitamin B9), along with vitamins B6 and B12, are part of the methylation cycle. As discussed in this Truth Series in the article by Dr Robyn Murphy, one goal of this cycle is to reduce and recycle a compound called homocysteine which can cause inflammation, damage and malformations in the developing fetus. Folic acid, B6 and B12 help to prevent this.
Most notably, folic acid is critical during pre-conception and early pregnancy to prevent neural tube defects: issues with the development of the brain and spinal cord. For this reason, public health initiatives fortified grain-based foods with folic acid, and since then we have successfully reduced the incidence of these defects. However, there are concerns regarding harmful developmental effects of too much folic acid, especially when you combine dietary folate with supplemental folic acid.
THE FORMS OF FOLIC ACID
First, it’s important to understand the differences between dietary and supplemental forms of these vitamins and note that they are not all equal. For example, folate can be supplemented in a synthetic “folic acid” form, or the more active, bioavailable form, 5-methyltetrahydrofolate (5-MTHF). Both can be called folic acid, but they are not the same molecule, and therefore the body treats them differently.
Most commercially available supplements use the synthetic form of folic acid which must be transformed twice (into dihydrofolate and tetrahydrofolate) by particular enzymes.
These forms aren’t used in the same way as natural folate and therefore often remain unmetabolized in a less useful state in the blood.
Some researchers have voiced concerns that too much of this unmetabolized folic acid can lead to issues in infants and children, such as increased fat mass and insulin resistance1, increased seizure activity, and behavioural dysregulation.2 It is believed that folate transformation pathways become saturated when more than 400mcg per day is ingested, after which folic acid is transported into the blood without being converted to the active form.3
HIGH FOLIC ACID CAN MASK A B12 DEFICIENCY
When addressing concerns about folic acid intake, the second problem researchers make is not accounting for several other relevant factors, including B12 levels. It is well understood that high folic acid levels can mask a B12 deficiency. This has been the case in some of these studies, where folic acid levels may have been high, but B12 levels were low or deficient. Therefore, the health issues we see in these studies could be due to too much circulating unmetabolized folic acid or, deficient B12 levels. Mothers with a B12 deficiency would have affected the study results.
Ideally, future research will compare the effects of using the biologically active 5-MTHF form, which has already displayed proven additional benefits: reducing the potential for masking a B12 deficiency while eliminating the issue of mutations in folic acid enzymes. 5-MTHF also prevents the issue of having unmetabolized folic acid in the bloodstream.
The risk of autism seems to correlate more closely to the types of genetic mutations that affect the enzymes that transform and activate vitamins and nutrients. As well, we need to be mindful of how these B vitamins interact and work together. A high intake of folic acid itself may not be harmful, but excessive doses of synthetic forms with correspondingly low levels of vitamin B12 could increase health risks.
ROLES OF FOLIC ACID ON NEURODEVELOPMENT DURING PREGNANCY
Researchers have looked explicitly at the association between folic acid supplementation in pregnancy and outcomes of autism spectrum disorders (ASD), developmental delay, cognition, attention, and other emotional and behavioural concerns in children. In one systematic review of 22 original papers, 15 showed that folic acid reduced the risk of infants and children developing ASD, and 6 studies found no difference.2
A study of over 85,000 children revealed that the rate of ASD in children whose mothers took folic acid was 0.1% compared to 0.2% in mothers who did not supplement. Other studies showed that the risk of developing ASD was lower in mothers who took 0.6-5mg of folic acid daily – one even showing that these children had increased scores for receptive and expressive communication by 18 months. However, one study did note a higher risk of ASD when mothers consumed amounts larger than 5mg daily.2
The authors of this review concluded that folic acid supplementation in pregnancy may protect against impaired neurodevelopment, including ASD in children, and may improve cognitive, intellectual, and motor function.
THE BOTTOM LINE ON FOLIC ACID AND AUTISM?
A folate deficiency before and in the first 12 weeks of pregnancy is associated with an increased risk of issues in neurodevelopment. Supplementation can reduce this risk by up to 70%.2The tolerable safe upper limit of folic acid supplementation is 1mg per day, and there seem to be no health risks associated with naturally-occurring folate in foods. The increased risk of ASD and health outcomes occur when synthetic folate is consumed in more substantial amounts (potentially >400mcg) by individuals with: a vitamin B12 deficiency, a genetic mutation in folate enzymes, or when daily doses exceed 5mg.
CANCER RISK AND B-VITAMINS
LUNG CANCER AND B-VITAMIN SUPPLEMENTATION
In addition to their role in the methylation cycle, B-Vitamins help produce the components of DNA. When B-Vitamins aren’t available, a substitute part goes into the DNA strand, causing breaks, disrupting repair, and can lead to cancer-like changes. These changes have been shown to occur when there are low levels of folic acid and B12, as well, with high levels of homocysteine.⁴ Because of this role, B vitamins have been considered protective against cancer, though confusingly, many studies have reported adverse effects of B vitamins on cancer risk.
As an example of a study that found a link between B supplementation and lung cancer risk, over 77,000 men and women between the ages of 50-76 years were asked to report their intake of all vitamin supplements used during the past 10-years (before baseline), including doses and brands.⁵ The study followed up on cancer outcomes of these subjects over an average of 6 years. The first issue is in relying on people to remember which supplements they took 10 years ago. Many patients can’t recall which brands of supplements they’re currently using, so having to rely on memory is a faulty way of collecting data.
Secondly, this study excluded people who had never smoked cigarettes because the incidence of lung cancer in that group was so low. So ultimately, this study only looked at the risk of lung cancer in cigarette smokers who were supplementing with B vitamins. More so, those with lung cancer were more likely to be current smokers, have more pack-years of smoking and have a history with chronic obstructive pulmonary disease (COPD) or cancer.5
The conclusion? Male smokers who took higher doses of vitamins B6 and B12 over 10 years had a 30-40% increased risk of developing lung cancer. This risk was not found in women.5 Let’s posit some reasons for this outcome.
As mentioned above, taking certain supplemental B-Vitamins can be beneficial in reducing the risk of cancers. Both methylcobalamin B12 and the 5-MTHF form of folate are methyl donors, and as such, actually, help protect against DNA damage (which can lead to gene mutations and cancer). However, in the presence of already mutated or abnormal cells (more common in male smokers) additional B vitamins could potentially lead to more rapid cell growth and therefore could theoretically promote the development and growth of cancer cells.
A controlled trial in Norway investigated cancer outcomes in men and women (mean age 62 years) taking B vitamins for over 3 years, following up with them years later.6 Although the authors concluded that folic acid and B12 supplementation increased the risk of cancer, their methods were flawed. Patients with a history of cancer were included, and all participants had ischemic heart disease. As well, 39% of participants were smokers (a higher percentage of smokers than in all of the United States).6 This abnormally high percentage of smokers creates a considerable problem as current smokers or those with a history of smoking are significantly more at risk of nutritional deficiencies. Smoking tobacco can destroy or disable nutrients such as vitamin B6, B12 and folic acid. The toxic components in cigarette smoke convert B12 back to its inactive form, leaving smokers with significantly higher amounts of inactive B12 compared to non-smokers.7 Therefore, B12 and its actions are relatively disrupted in those who smoke cigarettes, and these results cannot be applied to the general population.
POSITIVE STUDIES ON B VITAMINS AND THE PREVENTION OF CANCER
In northern China, a study of a population known to have low vitamin B2 (riboflavin) levels found that the incidence of oesophageal cancer was reduced when salt was fortified with riboflavin(4). Additionally, higher blood levels of riboflavin were significantly associated with a reduced risk of this type of cancer. However, the authors noted that this effect might be limited in adults who start supplementation later in life, and especially after a lifetime of nutritional deficiency. Another review study found that dietary folic acid reduced the risk of oesophageal cancer by 12% for every 100mcg increase in folic acid dosing.⁸ Another study found that each 1mg per day increase of vitamin B6 decreased the risk of oesophageal cancer by 16%.⁹ Lastly, a European study found that higher dietary folate intakes were associated with lower risks of sex hormone-related breast cancers.10
THE BOTTOM LINE ON B VITAMINS AND CANCER RISK
From the studies listed in this article, it would be irresponsible to say that B vitamins increase the risk of cancer. Caution should be exercised in those with a history of cancer, a history of smoking, and those with a significant risk of DNA damage from life-long nutritional deficiencies. There is evidence to show that B-Vitamin supplementation is generally beneficial for reducing cancer risk, with potentially better results when consuming the active methylated forms of B12 and folic acid: methylcobalamin and 5-MTHF, respectively.⁵
1. Wiens D, DeSoto MC. “Is high folic acid intake a risk factor for autism? – A review.” Brain Sci. 2017 Nov; 7(11): pii:E149. doi: 10.3390/ brainsci7110149.
2. Gao Y, Sheng C, Xie RH, Sun W, Asztalos E, Moddemann D, Zwaigenbaum L, Walker M, Wen SW. “New perspective on impact of folic acid supplementation during pregnancy on neurodevelopment/autism in the offspring children – a systematic review.” PLoS One. 2016 Nov; 11(11): e0165626
3. Choi JH, Yates Z, Veysey, M, Heo YR, Lucock M. “Contemporary issues surrounding folic Acid fortification initiatives” Prev Nutr Food Sci. 2014 Dec; 19(4): 247-60
4. Ren J, Murphy G, Fan J, Dawsey SM, Taylor PR, Selhub J, Qiao Y, Abnet CC. “Prospective study of serum B vitamins and oesophageal and gastric cancers in China.” Sci Rep. 2016 Oct; 6:35281
5. Brasky TM, White E, Chen CL. “Long-term supplemental, one-carbon metabolism-related vitamin B use in relation to lung cancer risk in the vitamins and lifestyle (VITAL) cohort.” J Clin Oncol. 2017 Oct; 35(30): 3440-8
6. Ebbing M, Bonaa KH, Nygard O, Arnesen E, Ueland PM, Nordrehaug JE, Rasmussen K, Niolstad
I, Refsum H, Nilsen DW, Tverdal A, Meyer K, Vollset SE. “Cancer incidence and mortality after treatment with folic acid and vitamin B12.” JAMA. 2009 Nov; 302(19): 2119-26
7. Shekoohi N, Javanbakht MH, Sohrabi M, Zarei M, Mohammadi H, Dialali M. “Smoking discriminately changes the serum active and non-active forms of vitamin B12.” Acta Med Iran. 2017 Jun; 55(6): 389-94
8. Zhao Y, Guo C, Hu H, Zheng L, Ma J, Jiang L, Zhao E, Li H. “Folate intake, serum folate levels and esophageal cancer risk: an overall and dose-response meta-analysis.” Oncotarget. 2017 Feb; 8(6): 10458-69
9. Qiang Y, Li Q, Xin Y, Fang X, Tian Y, Ma J, Wang J, Wang Q, Zhang R, Wang J, Wang F. “Intake of dietary one-carbon metabolism-related B vitamins and the risk of esophageal cancer: a dose-response meta-analysis” Nutrients. 2018 Jun; 10(7): pii: E835
10. – De Battle J, Ferrari P, Chajes V, et al. “Dietary folate intake and breast cancer risk: European prospective investigation into cancer and nutrition.” J Natl Cancer Inst. 2014 Dec; 107(1): 367
CAUTION SHOULD BE EXERCISED IN THOSE WITH A HISTORY OF CANCER, A HISTORY OF SMOKING, AND THOSE WITH A SIGNIFICANT RISK OF DNA DAMAGE FROM LIFE-LONG NUTRITIONAL DEFICIENCIES.